The aim of this renewal grant application is to continue the discovery of new marine natural products with activity against solid tumors, especially colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. Our focus is on tumors with relative insensitivity to most of the known anticancer drugs. Attention is on the natural products from chemically rich organisms. This includes sponges, sponge-derived fungi, and sediment-derived fungi. The program continues the effective ongoing collaboration between the Natural Products group at U. of California Santa Cruz (UCSC) lead by Prof. Crews and the Experimental Therapeutics Program at the Henry Ford Cancer Center (HFCC) lead by Prof. Valeriote. This research will extend the evaluation of the natural products being discovered at UCSC through their testing in the cellular screens at HFCC and in a new yeast-based assay to be carried out at UCSC. The aims for the next grant period are: 1. To use sponges as the source for new bioactive, small biomolecules employing the mammalian cell, yeast-based, or enzyme assays. 2. To use sponge-derived fungi as a source for new active, small biomolecules employing the mammalian cell, yeast-based, or enzyme assays. 3. To use sediment-derived fungi as a source for new active, small biomolecules employing the mammalian cell, yeast-based, or enzyme assays. 4. To use the unique cytotoxicity disk diffusion assay as a primary screen to identify extracts with solid tumor selectivity for fractionation. 5. To make use of a yeast halo assay that includes synthetic lethality profiling to guide further work on marine extracts, fractions and library pure compounds by targeting for methionine aminopeptidases (MetAPs). 6. To efficiently isolate and characterize compounds by bioassay guided isolation of the 2% per year active hits identified in our two screens. 7. To engage in pharmacology studies on as many as five compounds annually.